CT251 / 14 - Phase 1/2 study of HST-1011, an oral CBL-B inhibitor, alone and in combination with anti-PD1 in patients with advanced solid tumors

Background: The E3 ligase Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is a master negative regulator of the immune system and thus an attractive target to address suboptimal outcomes to immune checkpoint inhibitors (ICI). CBL-B controls T-cell/NK cell activation and co-stimulatory pathways, including the signaling threshold for T-cell receptor (TCR) activation. CBL-B inhibition uncouples TCR stimulation from the requirement for CD28 co-stimulation while reducing T-cell susceptibility to immunosuppression mediated by PD1, immunosuppressive cytokines, and Treg cells. Accordingly, targeting CBL-B may enable immune activation even in tumors with low antigen levels, low intratumoral inflammation, inadequate co-stimulation and/or active immunosuppression associated with poor response/resistance to existing ICIs. HST-1011 is a novel, potent, selective, orally bioavailable allosteric small molecule CBL-B inhibitor that has been shown to robustly increase anti-tumor immunity in vitro and in vivo, including in model systems where other ICIs have minimal effect.Methods: SOLAR1 (NCT05662397) is a first-in-human, multicenter Ph1/2 trial investigating safety and tolerability (primary endpoint), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy (secondary endpoints) of HST-1011 monotherapy and an HST-1011/PD1 inhibitor combination. HST-1011 will be given orally while the PD1 inhibitor cemiplimab will be administered intravenously.Eligibility: Patients with advanced solid tumors and progression on standard of care diagnosed with a) tumor types for which PD-(L)1 therapies are approved with documented PD-(L)1 refractory/resistant disease, including patients with best response of stable disease for  6 months while on a PD-(L)1, OR b) selected tumor types in which patients may be naïve to anti-PD(L)1 (platinum-resistant ovarian cancer, metastatic castration-resistant prostate cancer without bony lesions, rectal cancer, anal cancer).Study Design: Ph1, Part A1: HST-1011 monotherapy dose escalation, utilizing a Bayesian optimal interval design (BOIN). Optional dosing cohorts will assess alternative dosing strategies. Ph1, Part A2: HST-1011 monotherapy dose optimization with up to 4 cohorts utilizing dose(s)/schedule(s) deemed safe in Part A1 but focused on histology-specific patient populations to generate additional PK, PD, and efficacy data within a potential Recommended Phase 2 Dose (RP2D) range. Ph1, Part B: HST-1011 dose escalation in combination with cemiplimab, as in Part A1 with a BOIN design and optional dosing cohorts.Biomarkers: Target engagement and PD will be assessed via a) serial monitoring of cytokines/chemokines and transcriptional profiles; b) peripheral immune cell profiling; and c) in-depth analysis of screening and on-treatment tumor biopsies. The study is open with competitive enrollment.